Clinical Benefit, Price, and Uptake for Cancer Biosimilars vs Reference Drugs in China

This systematic review and meta-analysis examines clinical benefits, costs, and uptake rates of approved cancer biosimilars of bevacizumab, rituximab, and trastuzumab compared with their corresponding reference drugs in China vs other countries.


Eligibility criteria
Participants: the patient was diagnosed with a malignant cancer that met the criteria of international guidelines. We did not limit the age, sex, number of lines of treatment, stage of the cancer, and other primary demographic characteristics of the patients with the cancer.
Intervention and Comparators: the intervention group was any of the rituximab biosimilars, trastuzumab biosimilars, and bevacizumab biosimilars (As of February 2023, only these three therapeutic cancer biosimilars have been approved in China). The comparators were their reference drug. We did not have any restrictions on dosage, treatment duration, treatment regimen, or number of patients included.
Study designs: we included randomized controlled trials (RCT) and cohort studies (comparative studies of biosimilars and originator drugs). The RCT was limited to explicit pre-specification for a non-inferiority or equivalence trial design. In addition, the primary endpoints of randomized controlled trials should include at least one of the efficacy endpoints. For the cohort studies, we did not restrict the study design (equipotent or noninferiority) and did not set out to have at least one primary efficacy endpoint, considering the evidence from the cohort studies as complementary evidence to the RCT.
Exclusion criteria (1) Non-comparative studies (e.g., reviews, expert commentaries, editorials, and clinical guidelines); (2) Studies without comparators; (3) The primary endpoints of the randomized controlled trials were pharmacokinetic parameters or safety; (4) The data for the cohort study design were derived from survey research.

eAppendix 2. Evidence sources and search strategy.
We conducted a systematic search based on PICO items in Embase, PubMed, Cochrane Library and ClinicalTrials.gov from database inception to February 1, 2023. XXL and XD were responsible for screening documents independently that met the inclusion criteria by title, abstract, and full text. If there was an inconsistency, it is resolved by the third reviewer.
Participants: Carcinoma or cancer or adenocarcinoma or tumor or oncology or neoplasm or malignant or lymphoma.
Comparators: Avastin or bevacizumab or Herceptin or trastuzumab or Rituxan or Rituximab or reference or originator or brand name or brand-name.
Study designs: Compared or comparison or compare or contrast or versus or equivalence or switching or equivalent or equivalence or equivalence or comparing.
The research strategy was similar to the previous study [JAMA Oncol. 2022;8(4):537-545] and the search strategy in this study as follow:
The Chinese healthcare system is established under a multi-tiered governance structure, involving the central, provincial, regional, and county governments 1,2 . The majority of drug procurement occurs through centralized bidding at the provincial or city level, which may result in regional variations 1 . Therefore, XXL and XD extracted the winning prices of each biosimilar and originator drug between 2015-2022 from different provinces or cities and calculated the weighted average price of the drug using the number of population as weights. The exchange rate of the U.S. dollar to the Chinese yuan was 6.9. Similar to the previous study 1 , we adjusted the price of biosimilars and their reference drug based on the annual consumption index published by the National Bureau of Statistics of China given the effect of inflation.
The healthcare facilities are categorized into primary healthcare facilities, first, second and third level hospitals in China. Usually, a higher level means a greater level of treatment. In this study, we used the national hospital sales volume from Pharnexcloud databse module 3 , which covered the sales volume of cancer biosimilars in secondary and higher hospitals across the country, as no public database of drug sales volume was available. XXL and XD extracted the sales volume of each cancer biosimilar and originator drugs for each quarter since the biosimilar was introduced to the market. For multiple biosimilars that were approved (e.g. eight bevacizumab biosimilars were approved in China), we aggregated the sales volume of these biosimilars. The annual uptake rate for biosimilars is calculated by dividing the one-year sales of biosimilars by the one-year sales of their reference drugs.
The cut-off date for price uptake rates of biosimilars was December 31, 2022.

Rarely occur
In January, 2019, Celltrion won two appeal cases claiming that Roche's patent for trastuzumab for the treatment of HER2-positive breast cancer was invalid;Tokyo District Court dismissed Genentech's claim against Sandoz-Kirin to prohibit the marketing of a rituximab biosimilar

Indication extrapolation
Primary consideration is given to core patents, with more limited impact of patents on indications; Exclusivity periods have not been established Impact of core and indication patents; Impact of exclusivity period (especially for 7-year orphan drug designation) Impact of core and indication patents; Impact of exclusivity period Impact of core and indication patents; Impact of exclusivity period.

Reimbursement policy
Determined Study duration is defined as the period from the period of participants will be followed and observed to assess the occurrence of specific outcomes. Abbreviations: NA, not available; ORR, objective response rate; pCR, pathologic complete response; PFS, progression-free survival.

First Author Year
Representativeness of the exposed cohort Selection of the non-exposed cohort Liu et al. 49 2022 The green, yellow and red colours indicates low risk, some concerns and high risk of bias, respectively； a Total scores (risk of bias): scoring from 7-9: high quality; Scoring from 4-6: high risk of bias; Scoring from 0-3: very high risk of bias.  The annual uptake rate for biosimilars is calculated by dividing the one-year sales of biosimilars by the one-year sales of their reference drugs. eTable 17. Reimbursable cancer indications for the biosimilars and reference drugs of bevacizumab, rituximab, and trastuzumab in the National Reimbursement Drug List in China (As of July 1, 2023).